Convergent Pathways Identified for Cannabis Use Disorder Across Diverse Ancestry Populations

Large disparities in the prevalence of cannabis use disorder (CUD) exist across ethnic groups in the U.S. Despite large GWAS meta-analyses identifying numerous genome-wide significant loci for CUD in European descents, little is known about other ethnic groups. While most GWAS and SNP-heritability studies focus on common genomic variants, rare and low-frequency variants, particularly those altering proteins, are known to be enriched for the heritability of complex traits and may contribute to disease in different ways across populations, either through converging or alternative pathways. In this study, we examined three populations including European Americans (EA) and two understudied populations: American Indians (AI) and Mexican Americans (MA). We focused on rare and low frequency functional variants in genes and pathways, and performed association analysis with CUD severity. We identified 10 significant loci in AI, the ARSA gene in MA, three significant pathways in MA, and one in EA associated with CUD severity. Notably, pathways related to arylsulfatases activation and heparan sulfate degradation were supported by both EA and MA, with additional evidence from AI. The integrin beta-1 cell surface interaction pathway, involved in cell adhesion, was uniquely significant in MA. Several immune-related pathways were also found, including an autoimmune condition significant in MA with evidence from EA as well, and a p38-gamma/delta mediated signaling pathway supported across all three cohorts. Although each population displayed distinct pathways linked to CUD, overlapping genes in top pathways suggested shared genetic factors, further highlighting the importance of considering diverse populations in genetic research on cannabis use disorder.